Project Summary/Abstract This project will investigate how the neocortex controls sensory processing in the thalamus. The neocortex and thalamus together constitute the majority of the mammalian brain and are crucial for sensation, motor control, and cognitive function. Virtually all sensory information enters the neocortex by way of the thalamus. The neocortex also provides massive top-down input to the thalamus. ?Corticothalamic? (CT) projections outnumber ascending ?thalamocortical? projections 10:1. This suggests that the cortex has a strong influence on thalamic activity and, thereby, on its own sensory input. Indeed, altered thalamic-cortical communication has been associated with disorders such as epilepsy and schizophrenia. Despite its obvious importance, a thorough understanding of CT function has been elusive. It is generally assumed that the cortex influences thalamic throughput by modulating the excitability of thalamic relay cells. However, in previous studies the scale and even the sign of modulation have varied. The complexity of CT circuits has long been an impediment to understanding them, but powerful genetic and optical tools can now be utilized to drive major advances. The central goal of our proposal is to determine how top-down projections from the neocortex influence thalamic sensory processing at the level of cellular, synaptic, and circuit mechanisms. We address this goal in three aims by utilizing the widely studied and technically tractable somatosensory system of the mouse. Aim 1 will focus on the extensive layer 6 CT system. In awake animals performing a sensory detection task, we will test our hypothesis that the TC system bidirectionally controls thalamic sensory processing, and that the sign of control is dynamically determined by layer 6 cell spike rates, short-term synaptic plasticity, and behavioral state. Aim 2 will focus on the layer 5 CT system, which is structurally distinct. Layer 5 CT projections, unlike those of layer 6, bypass the inhibitory thalamic reticular nucleus and the primary thalamic relay nuclei and make strong driver-type synapses in higher-order thalamic nuclei. Using specific Cre-expressing mouse lines and optogenetics, we will test the prediction that the dynamic balance of thalamic excitation and inhibition caused by layer 5 CT circuitry is dramatically different from that of layer 6. We will also characterize how these two CT circuits interact to produce integrated effects. Aim 3 will examine how the CT cells are themselves controlled, focusing on effects of diverse thalamic inputs. We, and others, have shown that neurons in layers 5 and 6 are powerfully innervated by thalamus, and that distinct thalamic nuclei have unique cortical projections. Here we will test the hypothesis that feed-forward inputs from first-order and second-order thalamic nuclei exert powerful but complementary control over CT cells of layers 5 and 6. Our project will provide much-needed insight about how CT systems influence thalamic processing. Such information will be essential for understanding neurological disorders involving CT communication.